The compounds of formula I are described as 11,12-secoprostaglandins because of their structural relationship to the naturally occurring prostaglandins.
The prostaglandins constitute a biologically prominent class of naturally occurring, highly functionalized C.sub.20 fatty acids which are anabolized readily in a diverse array of mammalian tissues from three essential fatty acids; namely, 8,11,14-eicosatrienoic acid, 5,8,11, 14-eicosatetraenoic acid and 5,8,11,14,17-eicosapentaenoic acid. Each known prostaglandin is a formal derivative of the parent compound, termed "prostanoic acid;" the latter is a C.sub.20 fatty acid covalently bridged between carbons 8 and 12 such as to form a trans, vicinally-substituted cyclopentane in which the carboxy-bearing side chain is "alpha" or below the plane of the ring and the other side chain is "beta" or above the plane of the ring as depicted in formula III: ##STR3##
The six known primary prostaglandins, PGE.sub.1, PGE.sub.2, PGE.sub.3, PGF.sub.1.alpha. ,PGF.sub.2.alpha. , and PGF.sub.3.alpha. resulting directly from anabolism of the above cited essential fatty acids via the action of prostaglandin synthetase, as well as the three prostaglandins resulting from in vivo dehydration of the PGE's, i.e., PGA.sub.1, PGA.sub.2, and PGA.sub.3, are divided into three groups; namely, the PGE, PGF, and PGA series on the basis of three distinct cyclopentane nuclear substitution patterns as illustrated as follows:
______________________________________ ##STR4## ##STR5## ##STR6## PGE nucleus PGF.sub..alpha. nucleus PGA nucleus ______________________________________ PG R.sub.a R.sub.b ______________________________________ E.sub.1, F.sub.1, A.sub.1 ##STR7## ##STR8## E.sub.2, F.sub.2, A.sub.2 ##STR9## ##STR10## E.sub.3, F.sub.3, A.sub.3 ##STR11## ##STR12## E.sub.o, F.sub.o, A.sub.o ##STR13## ##STR14##
It should be noted that the Arabic subscripts designate the number of carbon-carbon double bonds in the designated compound and that the Greek subscript used in the PGF series designates the sterochemistry of the C-9 hydroxyl group.
Although the prostaglandins were discovered independently in the mid-1930's by Goldblatt [J. Chem. Soc. Chem. Ind. Lond., 52, 1056 (1933)] in England and Von Euler [Arch. Exp. Path. Pharmark., 175, 78 (1934)] in Sweden, these complex natural products received little attention from the scientific community until the early 1960's which coincides with the advent of modern instrumentation (e.g., mass spectrometry) which, in turn, was requisite for their successful isolation and structural elucidation by Bergstrom and colleagues [see Angew. Chem. Int. Ed., 4, 410 (1965) and references cited therein for an account of this work]. Within the last decade, a massive international scientific effort has been expended in developing both biosynthetic and chemical routes to the prostaglandins and, subsequently, in investigating of their biological activities. During this period, prostaglandins have been shown to occur extensively in low concentrations in a myriad of mammalian tissues where they are both rapidly anabolized and catabolized and to exhibit a vast spectrum of pharmacological activities including prominent roles in (a) functional hyperemia, (b) the inflammatory response, (c) the central nervous system, (d) transport of water and electrolytes, and (e) regulation of cyclic AMP. Further details concerning the prostaglandins can be found in recent reviews of their chemistry [J. E. Pike, Fortschr. Chem. Org. Naturst., 28, 313 (1970) and G. F. Bundy, A. Rep. in Med. Chem., 7, 157 (1972)], biochemistry [J. W. Hinman, A. Rev. Biochem., 41, 161 (1972)], pharmacology [J. R. Weeks, A. Rev. Pharm., 12, 317 (1972)], physiological significance [E. W. Horton, Physiol. Rev., 49, 122 (1969)] and general clinical application [J. W. Hinman, Postgrad. Med. J., 46, 562 (1970)].
The potential application of natural prostaglandins as medicinally useful therapeutic agents in various mammalian disease states is obvious but suffers from three formidable major disadvantages, namely, (a) prostaglandins are known to be rapidly metabolized in vivo in various mammalian tissues to a variety of metabolites which are devoid of the desired original biological activities, (b) the natural prostaglandins are inherently devoid of biological specificity which is requisite for a successful drug, and (c) although limited quantities of prostaglandins are presently produced by both chemical and biochemical processes, their production cost is extremely high; and, consequently, their availability is quite restricted.
Our interest has, therefore, been to synthesize novel compounds structurally related to the natural prostaglandins but with the following unique advantages: (a) simplicity of synthesis leading to low cost of production; (b) specificity of biological activity which may be either of a prostaglandin-mimicking or prostaglandin-antagonizing type; (c) enhanced metabolic stability. The combination of these advantages serves to provide effective, orally and parenterally active therapeutic agents for the treatment of a variety of human and animal diseases. Included are applications in renal, cardiovascular, gastrointestinal, respiratory, and reproductive systems, and in the control of lipid metabolism, inflammation, blood clotting, skin diseases, and certain cancers.
More specifically, in the clinic, prostaglandin agonists can function as agents for improving renal function (e.g., renal vasodilation), antihypertensives, anti-ulcer agents, agents for fertility control, antithrombotics, antiasthmatics, antilipolytics, antineoplastic agents, and agents for the treatment of certain skin diseases.
Prostaglandin antagonists can function as anti-inflammatory agents, anti-diarrheal agents, antipyretics, agents for prevention of premature labor, and agents for the treatment of headache.
The compounds of the present invention are useful as pharmaceutically active compounds. Thus, these compounds are orally active in the treatment of conditions which are responsive to the actions of the natural prostaglandins. It is of course necessary to determine by routine laboratory testing which of the compounds of the present invention are most suitable for a specific end use. Some of the compounds of the invention have prostaglandin-like activity in that they mimic the effect of prostaglandin E.sub.1 in stimulating the formation of cyclic AMP in the mouse ovary in vitro.
The compounds of this invention are particularly useful for the treatment of hypertension. Certain of the compounds of the present invention are useful in lowering blood pressure in individuals with blood pressure higher than normal. Thus, for example, the compound 8-acetyl-12-hydroxy-8-phenylheptadecanoic acid is found to be effective in lowering blood pressure in laboratory animals (rats) which have blood pressure higher than that normally observed in such test animals.
Because of their biological activity and ready accessibility, the compounds of the invention are also useful in that they permit large scale animal testing, useful and necessary to understanding of these various disease conditions such as kidney impairment, ulcers, dwarfism caused by poorly-functioning pituitary glands, stroke (thrombus formation), and the like. It will be appreciated that not all of the compounds of this invention have these biological activities to the same degree, but the choice of any particular ones for any given purpose will depend upon several factors including the disease state to be treated.
The compounds of this invention can be administered either topically or systemically, i.e., intravenously, subcutaneously, intramuscularly, orally, rectally, or by aerosolization in the form of sterile implants for long action. They can be formulated in any of a number of pharmaceutical compositions and non-toxic carriers to this end.
The pharmaceutical compositions can be sterile injectable suspensions or solutions, or solid orally administrable pharmaceutically acceptable tablets or capsules; the compositions can also be intended for sublingual administration, or for suppository use. It is especially advantageous to formulate compositions in dosage unit forms for ease and economy of administration and uniformity of dosage. "Dosage unit form" as a term used herein refers to physically discrete units suitable as unitary dosages for animal and human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired biological effect in association with the required pharmaceutical means.
Illustratively, a sterile injectable composition can be in the form of aqueous or oleagenous suspensions or solutions.
The sterile injectable composition can be aqueous or oleagenous suspension or solution. Suspensions can be formulated according to the known art using suitable dispersing and wetting agents and suspending agents. Solutions are similarly prepared from the salt form of the compound. For the laboratory animals, we prefer to use incomplete Freund's adjuvant or sterile saline (9%) as carrier. For human parenteral use, such as intramuscularly, intravenously, or by regional perfusion, the diluent can be a sterile aqueous vehicle containing a preservative; for example, methylparaben, propylparaben, phenol, and chlorobutanol. The aqueous vehicle can also contain sodium chloride, preferably in an amount to be isotonic; as well as a suspending agent, for example, gum arabic, polyvinyl pyrrolidone, methyl cellulose, acetylated monoglyceride (available commercially as Myvacet from Distillation Products Industry, a division of Eastman Kodak Company), monomethyl glyceride, dimethyl glyceride or a moderately high molecular weight polysorbitan (commercially available under the tradenames Tween or Span from Atlas Powder Company, Wilmington, Delaware). Other materials employed in the preparation of chemotherapeutic compositions containing the compound may include glutathione, 1,2-propanediol, glycerol and glucose. Additionally, the pH of the composition is adjusted by use of an aqueous solution such as tris(hydroxymethyl)aminomethane (tris buffer).
Oily pharmaceutical carriers can also be used, since they dissolve the compound and permit high doses. Many oily carriers are commonly employed in pharmaceutical use, such as, for example, mineral oil, lard, cottonseed oil, peanut oil, sesame oil, or the like.
It is preferred to prepare the compositions, whether aqueous or oils, in a concentration in the range of from 2-50 mg./ml. Lower concentrations than 50 mg./mg. are difficult to maintain and are preferably avoided.
Oral administration forms of the drug can also be prepared for laboratory animals or human patients provided that they are encapsulated for delivery in the gut. The drug is subject to enzymatic breakdown in the acid environment of the stomach. The same dosage levels can be used as for injectable forms; however, even higher levels can be used to compensate for biodegradation in the transport. Generally, a solid unit dosage form can be prepared containing from 0.5 mg. to 25 mg. active ingredient.
Whatever the mode of administration, doses in the range of about 0.10 to 20 milligrams per kilogram of body weight administered one to four times per day are used. The exact dose depending on the age, weight, and condition of the patient, and the frequency and route of administration.
The low cost and ready accessibility of the compounds of this invention make them particulaly promising for applications in veterinary medicine in which field their utilities are comparable to those in human medicine.
There are a number of inter-related processes useful in preparing the compounds of Formula I. These can all be described as the sub-synthesis of each of the three main moieties of the molecule, i.e., the (CH.sub.2).sub.4 AR chain, the ##STR15## chain, and the Q group which are attached to an asymmetric carbon, and their reaction(s) to form the desired end product.
One major process utilizes as starting materials compounds in which only the Q group is lacking, i.e., ##STR16##
When using these compounds of Formula IV, R is defined to be either a carboxy group or a blocked carboxy group, i.e., a lower alkyl ester wherein lower alkyl is 1-6 carbon atoms. Compounds of this structure are not part of this invention, but are claimed in co-pending U.S. Ser. No. 302,365, filed October 30, 1972, now abandoned in the names of Cragoe, Bicking and Smith, and in a continuation-in-part application of that application, Ser. No. 389,901, filed Aug. 23, 1973, now abandoned, and in its second continuation-in-part application, Ser. No. 669,118 filed Mar. 22, 1976, in the names of the same inventors.
These starting materials of Formula IV where R is carboxy are reacted with cupric chloride and lithium chloride to yield compounds of Formula I wherein Q is chloro; and with cupric bromide and lithium bromide to yield compounds wherein Q is bromo. When compounds wherein Q is methyl are desired, the compounds of Formula IV where R is blocked carboxy as described above are first treated with molecular bromine. The products of this reaction (Q equals bromo) are reacted with dimethyl copper lithium (generated in situ) to give products of Formula IV where Q is methyl. The carboxy-blocking ester function can subsequently be removed by basic hydrolysis.
To prepare compounds of Formula I wherein Q is phenyl, a sequential synthesis of the molecule is employed.
First, the starting material is one of the following reagents: ##STR17## wherein X is halogen, preferably chlorine or bromine, and R.sup.3 and R.sup.4 are as defined in Formula I.
Reagent V is used to obtain final compounds of Formula I wherein R.sup.1 is hydrogen; the reagent VI is used when R.sup.1 is methyl in the desired final product.
Either of the desired reagents is reacted with phenyl acetone or a substituted phenyl acetone, viz., ##STR18## wherein W indicates an optional substituent (or substituents). Substituents which are suitable are halogens, e.g., chlorine, bromine, iodine, or fluorine; lower alkyl, e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like; lower alkoxy, as methoxy, ethoxy, propoxy, and the like. The substituent(s) can be ortho-, meta-, or para-position, and mono- or poly-substitution can be made. When there is poly-substituent, the substituents need not necessarily be the same.
The reaction between compounds V or VI and VII is conducted in the following manner:
Compound VII is treated with an equivalent of base such as sodium hydride, sodium ethoxide, sodium amide, or the like. The enolate anion thus produced is alkylated by reaction with either compound V or VI. This reaction is conducted in an inert solvent such as dimethylformamide, dimethylformamide:benzene (1:1) or diglyme, at a temperature ranging from 40.degree. to 120.degree. C. The reactants are employed in approximately equimolar amounts. The reaction is complete in 2-4 hours. The intermediate product(s) are then isolated: ##STR19## wherein W, R.sup.3, and R.sup.4 are as defined.
Either of these compounds VIII or IX are then treated with an equimolar amount of base, as NaH, NaOC.sub.2 H.sub.5, NaNH.sub.2, and then alkylated with the reagent: EQU X-(CH.sub.2).sub.4 -A-COOR.sup.8 X
wherein X is halogen, preferably bromine or chlorine, A is as defined in Formula I, and R.sup.8 is lower alkyl having 1-5 carbon atoms, preferably ethyl. This reaction is conducted in a similar manner as before, i.e., the reagents are employed in approximately equimolar amounts; the solvent employed is inert, such as DMF, DMF in benzene (1:1) or diglyme. Temperature can be between about 60.degree. C. to 120.degree. C. The reaction is complete within 12-72 hours.
The products isolated are the following: ##STR20## These are further treated to yield the final product of Formula I.
For example, compound XI is hydrogenated to remove the protecting )-benzyl group and then subjected to mild basic hydrolysis to hydrolyze the ester function and remove R.sup.8.
Compound XII is hydrated using a oxymercuration-demercuration process in which the compound is treated with mecuric acetate in aqueous tetrahydrofuran for a prolonged period to effect oxymercuration followed by treatment of the reaction mixture with sodium borohydride to effect demercuration. This product is: ##STR21## Mild basic hydrolysis (NaOH is aqueous methanol or ethanol) of the ester function of compound XIII yields the compounds of Formula I.
It should be pointed out that the exact order of reacting either of compounds V or VI with VII, then with X, is not critical, either V or VI or X can be the first reactant. Subsequently, the other of the reactants is reacted with the recovered intermediate. The order described is our preferred route, however.
It can be advantageous from a therapeutic standpoint to prepare compounds of Formula I in which the various asymmetric carbons are exclusively in a certain configuration. For instance, the asymmetric carbon bearing the R.sup.1 and OR.sup.2 group, in the natural prostaglandins, is in the S configuration; inversion of this center usually produces a reduction in biological activity, although sometimes a marked increase in biological specificity results. Compounds exclusively R and S can be prepared in these processes by using starting materials or intermediates which are optically active, i.e., resolved into their R and S isomeric forms.
These products as prepared in these processes can be derivatized in a variety of ways to yield other products of Formula I.
1. The fundamental processes yield compounds where R is carboxy. To obtain carboxy salts the acid products are dissolved in a solvent such as ethanol, methanol, glyme and the like and the solution treated with an appropriate alkali or alkaline earth hydroxide or alkoxide to yield the metal salt, or with an equivalent quantity of ammonia, amine or quaternary ammonium hydroxide to yield the amine salt. In each instance, the salt either separates from the solution and may be separated by filtration or, when the salt is soluble it may be recovered by evaporation of the solvent. Aqueous solutions of the carboxylic acid salts can be prepared by treating an aqueous suspension of the carboxylic acid with an equivalent amount of an alkaline earth hydroxide or oxide, alkali metal hydroxide, carbonate or bicarbonate, ammonia, an amine, or a quaternary ammonium hydroxide.
To obtain carboxy esters (i.e., compounds where R is alkoxycarbonyl) the acid products are treated in ether with an ethereal solution of the appropriate diazoalkane. For example, methyl esters are produced by reaction of the acid products with diazomethane. To obtain products where R is carbamoyl, substituted carbamoyl or carbazolyl the acid product is first converted to an active Woodward ester. For example, the acid product can be made to react with N-tert-butyl-5-methylisoxazolium perchlorate in acetonitrile in the presence of a base such as triethylamine to yield an active ester in which R is ##STR22## Active esters of this type can be reacted with ammonia to yield products of Formula I where R is carbamoyl, with primary or secondary amines or di-lower-alkylaminoalkylamines to yield products where R is substituted carbamoyl, i.e., --CONR.sup.6 R.sup.7, and with hydrazine to yield products where R is carbazolyl.
2. The fundamental processes yield products where R.sup.2 is hydrogen. In compounds containing no additional hydroxy group and in which R.sup.1 is hydrogen, reaction with formic acid, acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, pivalic anhydride and the like, without solvent and at temperatures from 25.degree. to 60.degree. C., gives compounds wherein R.sup.2 is formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, and pivaloyl, respectively.
Methods for obtaining optical antipodes of the compounds of this invention have been described supra, whereby one of the components of the molecule is preresolved prior to its assembly into the whole molecule. Other methods also can be employed; for example, mixtures of racemates may be separated by taking advantage of the physiochemical differences between the components using chromatography and/or fractional crystallization. The racemic products and intermediates of this invention can be resolved into their optically active components by any one of a number of methods of resolution which are well described in the chemical literature.
Those compounds which are carboxylic acids can be converted to the diastereoisomeric salts by treatment with an optically active base such as + or - .alpha.-methylbenzylamine, + or - .alpha.-(1-naphthyl)-ethylamine, bromine, cinchonine, cinchonidine, or quinine. These diastereoisomeric salts can be separated by fractional crystallization.
The carboxylic acids of this invention also can be converted to esters using an optically active alcohol, such as, estradiol-3-acetate, or d- or 1-methanol and the diastereoisomeric esters resolved by crystallization or by chromatographic separation.
Racemic carboxylic acids also may be resolved by reverse phase and absorption chromatography using an optically active support and absorbent.
Compounds of this invention which contain free hydroxyl groups can be esterified with acid chlorides or anhydrides derived from optically active acids, such as, (.dbd.)-10-camphorsulfonic acid, (.dbd.)-.alpha.-bromocamphorsulfonic acid, or d- or 1-6,6'-dinitrodiphenic acid to form esters which can be resolved by crystallization.
Another method of obtaining pure optical isomers involves incubation of the racemic mixture with certain microorganisms such as fungi, by processes well established in the art, and recovering the product formed by the enzymatic transformation.
The methods describes supra are especially effective if one applies the process to a compound where one asymmetric center has been preresolved by the techniques already described.
The preparation of the intermediates V, VI and X is described in co-pending U.S. Ser. No. 302,365, now abandoned, filed Oct. 30, 1972 in the names of Cragoe, Bicking and Smith in a continuation-in-part application, U.S. Ser. No. 389,901, filed Aug. 23, 1973, now abandoned, and its second C-I-P application Ser. No. 669,118 filed Mar. 22, 1976.
The intermediates VII are prepared by a process which has been described in the chemical literature (R.V. Heinzelman, "Organic Syntheses" Coll. Vol. IV, John Wiley & Sons, Inc., New York, New York, p. 573) and which may be outlined as follows and wherein W is as described previously: ##STR23##